We undertook this study to obtain a global appreciation of the current state of adult IEM medicine in the French-speaking part of Switzerland. Some numerical results, as presented below, were in line with those obtained in other countries and centres. However, we were struck by what looked like a high burden of disease in our patients, and this is the aspect we would like to emphasize.
Which are the limitations of our study? Firstly, patients with Fabry disease were not included in this study as they were followed at a parallel dedicated clinic. However, previous studies showed that Fabry disease was one of the most prevalent IEMs in adults with diagnosis almost exclusively in adulthood (12, 18). This may affect the interpretation of the disease frequencies and age group at diagnosis in our cohort and its comparison with previous studies. Secondly, some patients with IEMs in the French-speaking Switzerland may be followed by other specialists or centres and therefore were not included in our results; this may be particularly true for individuals with less severe forms. Thirdly, classification of IEM is variable according to the textbooks and literature. We based our criteria on a reference textbook for inherited metabolic disease in adult (19), the Vademecum Metabolicum (20) and the Saudubray classification (16) but are aware that it may differ from other classifications such as the MetabERN diseases group (European Reference Network for Inherited Metabolic Disorders) (21). Fourthly, not all the IEM are represented in our cohort (i.e. congenital disorders of glycosylation, some urea cycle disorders, few subtypes of mucopolysaccharidosis, glycogenosis and β-oxidation defect) which also significantly biases the interpretation of the results. For these reasons, we do not suggest that our figures are necessarily applicable to other settings and other countries. In spite of these shortcomings, we feel that our study offers some insights that may be worthy of reflection.
Comparison of the size of our clinic and its disease distribution to other clinics around the world
In 2015, The SSIEM Adult Metabolic Physician Group completed a survey of 15 centers worldwide with a total number of 6182 adult patients (18). The number of patients with confirmed metabolic diagnosis varied widely between centers (from 10 to 1940). London had the highest number of patients (1940), followed by Vancouver (795) and Amsterdam (600). At that time, no Swiss Center was included. Retrospectively our number of patients was close to the number of the Reference Centers for Inherited Metabolic Diseases in Lille, France (126), in Udine, Italy (117) and in Hamburg, Germany (155). Considering that the French-speaking part of Switzerland and the city of Hamburg both had a population of nearly 2 million in 2018, the rate of attendance is similar between these two clinics, confirming the plausibility of our data. As expected, the most frequent disorder was PKU (including hyperphenylalaninemia), representing 23 (18.3%) cases. This frequency is close to the Report of the SSIEM adult Group (20.6%) and a study from Perez-Lopez et al. (21.6%) where 500 cases of adult patients with IEM from Reference Centers in Spain were reviewed (12). The high prevalence of PKU may also be due to the fact that it has been the first disorder included in newborn screening programs(22). The prevalence of the other IEMs in this study is comparable to previous studies, notably with amino acid (protein) metabolism disorders being the most prevalent group (18). The lysosomal group was underrepresented on our cohort as Fabry patients are taken care of in a parallel dedicated clinic.
IEMs diagnosed in adulthood account for more than 30% of all diagnoses
37% of the patients were diagnosed after 16 years of age. This observation was similar to the SSIEM adult group report (42%) (18) and included mainly patients from the energy defect disease group and storage disorders. Adult-onset is frequent in mitochondrial disease where individual level of heteroplasmy and variable environment can trigger the disease at any age. In contrast, the majority of the patients in the small molecule disorders group were diagnosed in the neonatal period which is likely explained by newborn screening and the frequent onset of symptoms in the neonatal period. Of note, many of our historical patients had been diagnosed solely on biochemical grounds; with the advent of quasi-universal application of next-generation sequencing techniques, the recognition of variant forms with juvenile or adult onset will increase significantly (23, 24). Here, it must be remarked that many of these “adult” diagnoses were made because of astute observations or intuitions of individual physicians; we suspect that a large number of individuals still go unrecognized. Awareness of the indication for and availability of genetic testing remains fragmentary among physicians caring for adult patients.
More than 50% of patients present with medical complications
In spite of regular attendance of the metabolic clinic and good compliance with treatment, 51% of the patients developed medical complications during the time of the study. Specific IEM, particularly those involving energy deficiency (mitochondrial diseases) and storage disorders, can present with dysfunction of different systems, contributing to complications. Some of the patients, mainly from the small molecule disorder group, were susceptible to acute metabolic decompensation, which required urgent hospital admission for correction of the metabolic derangement. Reasons for decompensation were in line with known triggers such as infection, non-adherence to treatment, or prolonged exercise (25). Unfortunately, we observed several complications in patients for whom only conservative treatment is available with no disease-specific alternatives such as ERT of other.
The challenge continues after transition from pediatric to adult care
The transition process has been effective for the majority of patients in our cohort however a minority of patients has been lost to follow-up thereafter, highlighting that this period is fragile and needs careful attention such as described previously for other genetic and/or endocrine conditions (11, 26, 27). In summary, the overall pattern emerging from these observations are the following: patients diagnosed in the neonatal or paediatric period are diagnosed and treated much better today than was the case 50 years ago and many patients reach adolescence and adulthood; however, these patients have to navigate through a transition process that is fraught with perils. In addition, there is a growing number of patients who are diagnosed with an IEM in adult age. As adults, all these patients may enjoy periods of stability but decompensations are possible at any time and late-onset complications tend to appear as the patient with age. The chronic genetic disease continues to exact its toll inexorably.
Ongoing efforts to coordinate diagnosis and care of individuals with IEMs
Switzerland was one of the first countries to implement newborn screening 50 years ago (28); and in 2017, Switzerland was considered to have the third best standard of healthcare in the world (29). Despite this remarkable track record, the observations above indicate that there is much room for improvement. Specific programmes for rare diseases have been or are being implemented in several European countries. The majority of these programmes include a specific section on IEMs. In Switzerland, The National Coordination for Rare Diseases (Kosek) is mandated with the establishment of networks to improve the care of individuals affected by rare diseases. One of the pilot groups within the Kosek programme is focused on IEM. One of the requisites of the networking progress is to make sure that dedicated centers meet high standards of organization and accountability (30). Ultimately, national recognition should enable reference centers to integrate European reference networks (31). Nevertheless, we would like to suggest that national coordination will not work unless the individual centers are improved and strengthened.